【结 构 式】 |
【分子编号】30310 【品名】diethyl 2-methylmalonate 【CA登记号】609-08-5 |
【 分 子 式 】C8H14O4 【 分 子 量 】174.19676 【元素组成】C 55.16% H 8.1% O 36.74% |
合成路线1
该中间体在本合成路线中的序号:(B)The reaction of 2-thiophenecarbonyl chloride (I) with fluorobenzene (A) by means of AlCl3 gives (4-fluorophenyl)(2-thienyl)ketone (II), which is then condensed with diethyl methylmalonate (B) by means of NaH in benzene-HMPA to yield diethyl 2-methyl-2-[4-(2-thienylcarbonyl)phenyl]malonate (III); this product is finally hydrolyzed and partially decarboxylated with refluxing aqueous NaOH.
【1】 Van Daele, P.G.H.; et al.; Synthesis of alpha-methyl-4-(2-thienylcarbonyl)benzene acetic acid, suprofen and derivatives. Arzneim-Forsch Drug Res 1975, 25, 10, 1495-1501. |
【2】 Castaner, J.; Chatterjee, S.S.; Suprofen. Drugs Fut 1976, 1, 3, 148. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(A) | 17466 | Fluorobenzene | 462-06-6 | C6H5F | 详情 | 详情 |
(B) | 30310 | diethyl 2-methylmalonate | 609-08-5 | C8H14O4 | 详情 | 详情 |
(I) | 14103 | 2-Thiophenecarbonyl chloride | 5271-67-0 | C5H3ClOS | 详情 | 详情 |
(II) | 34018 | (4-fluorophenyl)(2-thienyl)methanone | 579-49-7 | C11H7FOS | 详情 | 详情 |
(III) | 34019 | diethyl 2-methyl-2-[4-(2-thienylcarbonyl)phenyl]malonate | C19H20O5S | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号:(XII)The reaction of ethyl 2-methylacetoacetate (X) with NH3 in ethanol in an autoclave at 80 C gives ethyl 3-amino-2-methylcrotonate (XI), which is cyclized with diethyl 2-methylmalonate (XII) yielding 2,4-dihydroxy-3,5,6-trimethylpyridine (XIII). The reaction of (XIII) with POCl3 at 150 C affords 2,4-dichloro-3,5,6-trimethylpyridine (XIV), which is partially dechlorinated with H2 over Pd/C in ethanol/H2SO4 giving 4-chloro-2,3,5-trimethylpyridine (XV). The reaction of (XV) with sodium methoxide in hot DMSO yields 4-methoxy-2,3,5-trimethylpyridine (XVI), which is oxidized with H2O2 in AcOH affording the corresponding N-oxide (XVIII). The reaction of (XVIII) with acetic anhydride in hot acetic acid provides the acetate ester (XIX), which is finally hydrolyzed in the usual way to the target intermediate the 4-methoxy-3,5-dimethylpyridine-2-methanol (VI). The intermediate 4-chloro-2,3,5-trimethylpyridine (XV), can be oxidized with H2O2 in AcOH as before to give the corresponding N-oxide (XVII), which is treated with sodium methoxide in DMSO/methanol affording the previously described 4-methoxy-2,3,5-trimethylpyridine N-oxide (XVIII).
【1】 Junek, H.; Mittelbach, M.; Schmidt, H.-W.; Uray, G. (Hassle Lakemedel AB); Chemical intermediates and method for their preparation. EP 0226558 . |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VI) | 18785 | (4-methoxy-3,5-dimethyl-2-pyridinyl)methanol | C9H13NO2 | 详情 | 详情 | |
(X) | 10362 | ethyl 2-methyl-3-oxobutanoate; ethyl 2-methylacetoacetate | 609-14-3 | C7H12O3 | 详情 | 详情 |
(XI) | 31576 | ethyl (Z)-3-amino-2-methyl-2-butenoate | C7H13NO2 | 详情 | 详情 | |
(XII) | 30310 | diethyl 2-methylmalonate | 609-08-5 | C8H14O4 | 详情 | 详情 |
(XIII) | 31577 | 3,5,6-trimethyl-2,4-pyridinediol | C8H11NO2 | 详情 | 详情 | |
(XIV) | 31578 | 2,4-dichloro-3,5,6-trimethylpyridine | C8H9Cl2N | 详情 | 详情 | |
(XV) | 31579 | 4-chloro-2,3,5-trimethylpyridine | C8H10ClN | 详情 | 详情 | |
(XVI) | 31580 | 4-methoxy-2,3,5-trimethylpyridine; methyl 2,3,5-trimethyl-4-pyridinyl ether | C9H13NO | 详情 | 详情 | |
(XVII) | 31582 | 4-chloro-2,3,5-trimethyl-1-pyridiniumolate | C8H10ClNO | 详情 | 详情 | |
(XVIII) | 31581 | 4-methoxy-2,3,5-trimethyl-1-pyridiniumolate | 86604-80-0 | C9H13NO2 | 详情 | 详情 |
(XIX) | 31583 | (4-methoxy-3,5-dimethyl-2-pyridinyl)methyl acetate | C11H15NO3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号:(IX)The malonic synthesis of 4-nitrochlorobenzene (VIII) with sodium diethyl methylmalonate (IX) (prepared with the corresponding malonic ester and NaH) in hot DMF gives diethyl (4-nitrophenyl)methylmalonate (X), which is reduced with H2 over Pd/C as before yielding diethyl (4-aminophenyl)methylmalonate (XI). The alkylation of (XI) with (VI) by means of NaHCO3 in refluxing ethanol affords diethyl [4-(2-methylallyl)aminophenyl]methylmalonate (XII), which is treated with sodium ethoxide in refluxing ethanol to yield ethyl 2-(4-[2-methylallylamino)phenyl]propionate (XIV). Finally, this compound is hydrolyzed with NaOH in refluxing ethanol. Partial hydrolysis of (XII) with NaOH in refluxing ethanol gives 2-[4-(2-methylallylamino)phenyl]methylmalonic acid (XIII), which is finally decarboxylated by treatment with refluxing aqueous HCl. The simultaneous hydrolysis and decarboxylation of (XII) with NaOH in refluxing ethanol also gives the title product.
【1】 Dumaitre, B.; et al.; Synthesis of some analgesic and antiinflammatory 4-aminophenylacetic and 4-aminophenylacetic and 2-(4-aminophenyl)propionic acid derivatives. Eur J Med Chem - Chim Ther 1979, 14, 3, 207-214. |
【2】 Serradell, M.N.; Castaner, J.; Alminoprofen. Drugs Fut 1984, 9, 3, 165. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(VI) | 12127 | 3-Chloro-2-methyl-1-propene; Isobutenyl chloride | 563-47-3 | C4H7Cl | 详情 | 详情 |
(VIII) | 13909 | 1-Chloro-4-nitrobenzene; p-Nitrochlorobenzene | 100-00-5 | C6H4ClNO2 | 详情 | 详情 |
(IX) | 30310 | diethyl 2-methylmalonate | 609-08-5 | C8H14O4 | 详情 | 详情 |
(X) | 13910 | diethyl 2-methyl-2-(4-nitrophenyl)malonate | C14H17NO6 | 详情 | 详情 | |
(XI) | 30311 | diethyl 2-(4-aminophenyl)-2-methylmalonate | C14H19NO4 | 详情 | 详情 | |
(XII) | 30312 | diethyl 2-methyl-2-[4-[(2-methyl-2-propenyl)amino]phenyl]malonate | C18H25NO4 | 详情 | 详情 | |
(XIII) | 30313 | 2-methyl-2-[4-[(2-methyl-2-propenyl)amino]phenyl]malonic acid | C14H17NO4 | 详情 | 详情 | |
(XIV) | 30314 | ethyl 2-[4-[(2-methyl-2-propenyl)amino]phenyl]propanoate | C15H21NO2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号:(II)The condensation of cyclohexenone (I) with diethyl alpha-methylmalonate (II) by means of sodium ethoxide in ethanol gives diethyl alpha-methyl-3-oxocyclohexanemalonate (III), oil b.p.(0.8) = 149-52 C, n(20)(D) = 1.4660, which is hydrolyzed and decarboxylated with refluxing dioxane-HCl to yield alpha-methyl-3-oxocyclohexaneacetic acid (IV), oil, b.p.(0.7) = 164-6 C, n(20)(D) = 1.4794. The condensation of (IV) with 4-chlorophenylhydrazine (A) in acetic acid-water atfords 6-chloro-alpha-methyl-1,2,3,4-tetrahydrocarbazole-2-acetic acid (V), m.p. 193-202 C, which is esterified with ethanol-HCl to ethyl 6-chloro-alpha-methyl-1,2,3,4-tetrahydrocarbazole-2-acetate (VI) and aromatized with chloranil (B) in refluxing xylene to give ethyl 6-chloro-alpha-methylcarbazole-2-acetate (VII), m.p. 106.0-7.5 C. Finally, this ester is hydrolyzed with NaOH in refluxing ethanol.
【1】 Berger, L.; Corraz, A.J.; Carbazoles. ES 417167; ES 442684; ES 442685; US 3896145 . |
【2】 Weetman, D.F.; Castaner, J.; Carprofen. Drugs Fut 1977, 2, 1, 15. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(B) | 21891 | 2,3,5,6-Tetrachloro-1,4-benzoquinone; 2,3,5,6-Tetrachlorobenzo-1,4-quinone; p-Chloranil | 118-75-2 | C6Cl4O2 | 详情 | 详情 |
(A) | 33345 | 1-(4-chlorophenyl)hydrazine; 4-Chlorophenylhydrazine | 1073-70-7 | C6H7ClN2 | 详情 | 详情 |
(I) | 26253 | 2-cyclohexen-1-one;Cyclohex-2-enone;2-cyclohexenone | 930-68-7 | C6H8O | 详情 | 详情 |
(II) | 30310 | diethyl 2-methylmalonate | 609-08-5 | C8H14O4 | 详情 | 详情 |
(III) | 33625 | diethyl 2-methyl-2-(3-oxocyclohexyl)malonate | C14H22O5 | 详情 | 详情 | |
(IV) | 33626 | 2-(3-oxocyclohexyl)propionic acid | C9H14O3 | 详情 | 详情 | |
(V) | 33627 | 2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)propionic acid | C15H16ClNO2 | 详情 | 详情 | |
(VI) | 33628 | ethyl 2-(6-chloro-2,3,4,9-tetrahydro-1H-carbazol-2-yl)propanoate | C17H20ClNO2 | 详情 | 详情 | |
(VII) | 33629 | ethyl 2-(6-chloro-9H-carbazol-2-yl)propanoate | C17H16ClNO2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号:(II)Cyclization of 1-(2-fluoro-4-iodophenyl)-3-cyclopropyl-6-(methylamino)uracil (I) (optionally containing some 1-cyclopropyl regioisomer) with either diethyl 2-methylmalonate (II) in Ph2O at 220 °C or with 2-methylmalonic acid (III) in Ac2O at 100 °C yields the 5-hydroxypyrido[2,3-d]pyrimidine-2,4,7-trione derivative (IV) , which can be separated from its regioisomeric byproduct by crystallization from acetone . Treatment of compound (IV) with Tf2O in the presence of 2,6-lutidine in CHCl3 gives the corresponding triflate (V) . Similarly, reaction of (IV) with p-TsCl in the presence of Et3N and Me3N·HCl in acetonitrile produces tosylate (VI) . The condensation of triflate (V) with 3-nitroaniline (VII) at 130 °C furnishes the 5-(arylamino)pyrido[2,3-d]pyrimidine derivative (VIII), which undergoes rearrangement to the isomeric pyrido[4,3-d]pyrimidine (IX) in the presence of K2CO3 in MeOH/THF at 80 °C. Reduction of nitro compound (IX) by means of Na2S2O4 in DMF/H2O at 90 °C, followed by acetylation of the resulting amine with Ac2O in pyridine/CHCl3, leads to trametinib (X). Finally, crystallization of (X) from DMSO produces trametinib dimethyl sulfoxide solvate .
In an alternative procedure, condensation of either triflate (V) or tosylate (VI) with N-(3-aminophenyl)acetamide (XI) by means of 2,6-lutidine in DMA at 130 °C affords intermediate (XII), which upon rearrangement in the presence of NaOMe in THF/MeOH gives rise to the pyrido[4,3-d]pyrimidine compound (IX) .
【1】 Abe, H., Kikuchi, S., Hayakawa, K. et al. Discovery of a highly potent and selective MEK inhibitor: GSK1120212 (JTP-7407 DMSO solvate). ACS Med Chem Lett 2011, 2(4): 320. |
【2】 Sakai, T., Kawasaki, H., Abe, H. et al. (Japan Tobacco, Inc.). 5-Amino-2,4,7-trioxo-3,4,7,8-tetrahydro-2H-pyrido[2,3-d]pyrimidine derivatives and related compounds for the treatment of cancer. CN 101912400, EP 1761528, EP 1894932, EP 2298768, JP 2008201788, JP 2008501631, US 2006014768, US 7378423, US 2008312228, US 201024013, WO 2005121142. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XI) | 68368 | N-(3-aminophenyl)acetamide;3'-Aminoacetanilide | C8H10N2O | 详情 | 详情 | |
(I) | 68359 | 1-(2-fluoro-4-iodophenyl)-3-cyclopropyl-6-(methylamino)uracil;3-cyclopropyl-1-(2-fluoro-4-iodophenyl)-6-(methylamino)pyrimidine-2,4(1H,3H)-dione | C14H13FIN3O2 | 详情 | 详情 | |
(II) | 30310 | diethyl 2-methylmalonate | 609-08-5 | C8H14O4 | 详情 | 详情 |
(III) | 68360 | 2-methylmalonic acid | 516-05-2 | C4H6O4 | 详情 | 详情 |
(IV) | 68361 | 3-cyclopropyl-1-(3-fluoro-4-iodophenyl)-5-hydroxy-6,8-dimethylpyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione | C18H15FIN3O4 | 详情 | 详情 | |
(V) | 68362 | 3-cyclopropyl-1-(3-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl trifluoromethanesulfonate | C19H14F4IN3O6S | 详情 | 详情 | |
(VI) | 68363 | 3-cyclopropyl-1-(3-fluoro-4-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl 4-methylbenzenesulfonate | C25H21FIN3O6S | 详情 | 详情 | |
(VII) | 57781 | 1-Amino-3-Nitrobenzene; 3-Nitroaniline; m-Nitroaniline | 99-09-2 | C6H6N2O2 | 详情 | 详情 |
(VIII) | 68364 | 3-cyclopropyl-1-(3-fluoro-4-iodophenyl)-6,8-dimethyl-5-((3-nitrophenyl)amino)pyrido[2,3-d]pyrimidine-2,4,7(1H,3H,8H)-trione | C24H19FIN5O5 | 详情 | 详情 | |
(IX) | 68365 | 3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-1-(3-nitrophenyl)pyrido[4,3-d]pyrimidine-2,4,7(1H,3H,6H)-trione | C24H19FIN5O5 | 详情 | 详情 | |
(X) | 68366 | N-(3-(3-cyclopropyl-5-((2-fluoro-4-iodophenyl)amino)-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl)phenyl)acetamide | C26H23FIN5O4 | 详情 | 详情 | |
(XII) | 68367 | N-(3-((3-cyclopropyl-1-(3-fluoro-5-iodophenyl)-6,8-dimethyl-2,4,7-trioxo-1,2,3,4,7,8-hexahydropyrido[2,3-d]pyrimidin-5-yl)amino)phenyl)acetamide | C26H23FIN5O4 | 详情 | 详情 |